5-(4-ethylpiperazin-1-yl)pyridin-2-amine

The 4 - (2 - dimethyl carbonyl -2 - carbonyl - ethylamine) -2 - pyrimidine formic acid (1.26 g 1.2 eq), 5 - (4 - ethyl - piperazine -1 - yl) - piperidine -2 - amino (0.81 g 1 eq) and triethylamine (500 mul) in DMF (15 ml) in, then added HBTU (1.51 g 1.5 eq). The mixture stirring at room temperature to 16 hours, then EtOAc (50 ml) and saturated NaHCO3Solution (15 ml), and for separating each layer of EtOAc (2 × 15 ml) extraction the aqueous layer, the combined organic layer drying (MgSO4), Filtering and evaporation to dryness, the residue through the column chromatography purification, and to obtain white solid compound of 1.04 g (yield: 47%).4-(2-Dimethylcarbonyl-2-carbonyl-ethylamino)-2-pyrimidinecarboxylic acid (1.26 g, 1.2 eq), 5-(4-Ethyl-piperazin-1-yl)-piperidin-2-amino (0.81 g, 1 eq)And triethylamine (500 muL) in DMF (15 mL), Then HBTU (1.51 g, 1.5 eq) was added. The mixture was stirred at room temperature for 16 hours.Then with EtOAc (50 mL)And saturated NaHCO3 solution(15 mL), the layers were separated and EtOAc EtOAcThe combined organic layers were dried (MgSO4), filtered and evaporated.The residue was purified by column chromatography.1.04 g of the title compound 6 was obtained as a white solid(yield: 47%), Its nuclear magnetic resonance spectrum data is as follows:The 4 - (2 - chloro -3 - fluoro - pyrazine amino) -2 - pyrimidine formic acid (1.35 g 1.2 eq), 5 - (4 - ethyl - piperazine -1 - yl) - piperidine -2 - amino (0.81 g 1 eq) and triethylamine (500 mul) in DMF (15 ml) in, then added HBTU (1.51 g 1.5 eq). The mixture stirring at room temperature to 16 hours, then EtOAc (50 ml) and saturated NaHCO3Solution (15 ml), and for separating each layer of EtOAc (2 × 15 ml) extraction the aqueous layer, the combined organic layer dried (MgSO4), filtering and evaporation to dryness, the residue through the column chromatography purification, and to obtain white solid compound of 1.42 g (yield: 62%).4-(2-Chloro-3-fluoro-pyrazinylamino)-2-pyrimidinecarboxylic acid (1.35 g, 1.2 eq), 5-(4-Ethyl-piperazin-1-yl)-piperidin-2-amino (0.81 g, 1 eq) and triethylamine (500 muL)In DMF (15 mL) followed by HBTU (1.51 g, 1.5 eq).The mixture was stirred at room temperature for 16 hours.Then EtOAc (50 mL) and saturated NaHCO3 (15 mL)The layers were separated and the aqueous layer was extracted with EtOAc EtOAcThe combined organic layers were dried (MgSO4), filtered and evaporated.The residue was purified by column chromatography.1.42 g of the target compound 2 was obtained as a white solid(yield: 62%), Its nuclear magnetic resonance spectrum data is as follows:A reaction flask was charged with 321 mg (1 mmol) of 5-(2-chloro-5-fluoropyrimidin-4-yl)-3-ethyl-7-fluoro-2, 3-dimethyl-3H-indole prepared in Step 3, 206 mg (1 mmol) of 5-(4-ethylpiperazin-1-yl)pyridin-2-amino obtained in Step 2, 2 ml of 1, 4-dioxane, 650 mg (2 mmol) of Cs2CO3, 91mg (0.1mmol) of Pd2(dba)3, and 58mg (0.1mmol) of diphenylphosphine. The mixture was heated to 120C to conduct microwave reaction for 1 h. The reaction product was cooled to room temperature, added with 10ml of water and then extracted with ethyl acetate three times (40ml for each time). The organic phases were combined, washed once with 40 ml of saturated salt solution, dried with sodium sulfate, filtered, concentrated under reduced pressure and separated by silica gel column chromatography (DCM/MeOH = 10:1) to give the titled compound (49 mg, yellow solid), yield 10%. 1H-NMR(400MHz, CDCl3) delta9.25(br s, 1H), 8.46(d, 1H, J=3.2Hz), 8.28(d, 1H, J=9.2Hz), 8.17(d, 1H, J=2.0Hz), 7.90(d, 1H, J=11.2Hz), 7.82(s, 1H), 7.35(dd, 1H, J=9.2Hz, 2.8Hz), 3.20-3.18(m, 4H), 2.64-2.61(m, 4H), 2.51(q, 2H, J=6.8Hz), 2.31(s, 3H), 2.03-1.94(m, 1H), 1.89-1.82(m, 1H), 1.36(s, 3H), 1.13(t, 3H, J=7.2Hz), 0.48(t, 3H, J=7.2Hz). MS(ESI):m/z 492.3[M+H]+.General procedure: Pd2(dba)3 (86.4mg, 0.09mmol) and Xant-phos (109.2mg, 0.19mmol) were added under N2 to a solution of 154 1E (290.0mg, 0.94mmol), INT-7 (228.6mg, 1.04mmol), and 152 potassium phosphate (400.5mg, 1.88mmol) in 111 1, 4-dioxane (10mL). Then the mixture was reacted in the microwave at 150C for 1h. The mixture was cooled to RT, filtered, diluted with water (10mL), and extracted with DCM (10mL×3). The combined organic layers were washed with brine (30mL), dried over anhydrous Na2SO4, concentrated under a vacuum, and purified by preparative thin-layer chromatography to obtain 157 compound 1 (140.3mg; yield, 30%) as a yellow solid.General procedure: Pd2(dba)3 (86.4mg, 0.09mmol) and Xant-phos (109.2mg, 0.19mmol) were added under N2 to a solution of 154 1E (290.0mg, 0.94mmol), INT-7 (228.6mg, 1.04mmol), and 152 potassium phosphate (400.5mg, 1.88mmol) in 111 1, 4-dioxane (10mL). Then the mixture was reacted in the microwave at 150C for 1h. The mixture was cooled to RT, filtered, diluted with water (10mL), and extracted with DCM (10mL×3). The combined organic layers were washed with brine (30mL), dried over anhydrous Na2SO4, concentrated under a vacuum, and purified by preparative thin-layer chromatography to obtain 157 compound 1 (140.3mg; yield, 30%) as a yellow solid.General procedure: Pd2(dba)3 (86.4mg, 0.09mmol) and Xant-phos (109.2mg, 0.19mmol) were added under N2 to a solution of 154 1E (290.0mg, 0.94mmol), INT-7 (228.6mg, 1.04mmol), and 152 potassium phosphate (400.5mg, 1.88mmol) in 111 1, 4-dioxane (10mL). Then the mixture was reacted in the microwave at 150C for 1h. The mixture was cooled to RT, filtered, diluted with water (10mL), and extracted with DCM (10mL×3). The combined organic layers were washed with brine (30mL), dried over anhydrous Na2SO4, concentrated under a vacuum, and purified by preparative thin-layer chromatography to obtain 157 compound 1 (140.3mg; yield, 30%) as a yellow solid.General procedure: Pd2(dba)3 (86.4mg, 0.09mmol) and Xant-phos (109.2mg, 0.19mmol) were added under N2 to a solution of 154 1E (290.0mg, 0.94mmol), INT-7 (228.6mg, 1.04mmol), and 152 potassium phosphate (400.5mg, 1.88mmol) in 111 1, 4-dioxane (10mL). Then the mixture was reacted in the microwave at 150C for 1h. The mixture was cooled to RT, filtered, diluted with water (10mL), and extracted with DCM (10mL×3). The combined organic layers were washed with brine (30mL), dried over anhydrous Na2SO4, concentrated under a vacuum, and purified by preparative thin-layer chromatography to obtain 157 compound 1 (140.3mg; yield, 30%) as a yellow solid.Add to the reaction flask7- (2-chloro)Fluoro-pyrimidin-4-yl) -5-fluoro-2, 3-dihydro-1H-benzo [d]Pyrrole [1, 2-a] imidazole(200 mg, 0.6 mmol, prepared according to the procedure of Example 1)5- (4-ethylpiperazin-1-yl) pyridin-2-amine (123 mg, 0.6 mmol, prepared in second step)Cesium carbonate (390 mg, 1.2 mmol), Pd2 (dba) 3 (55 mg, 0.06 mmol)XantPhos (35 mg, 0.06 mmol) and anhydrous 1, 4-dioxane (5 mL).The mixture was stirred at 120 C for 12 hours.Cooled to room temperature, water (10 mL) and ethyl acetate (20 mL x 3) were added to the solution.The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, Filtered, concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 10: 1)The resulting residue was purified to give the title compound (50 mg, white solid)Yield 17%.Nitrogen was bubbled into a solution of compound 91 (65 mg, 0.3 mmol, 1 eq), Compound 14 (100 mg, 0.3 mmol, 1 eq; see Example 1), Pd2(dba)3 (27 mg, 0.03 mmol, 0.1 eq), Xantphos (36.3 mg, 0.063 mmol, 0.21 eq) and Cs2C03(195 mg, 0.6 mmol, 2 eq) in dioxane (28 mL) for 5 min. And then the mixture was stirred at 110 C for 2h. After completion, the mixture was cooled down to rt, diluted with DCM (50 mL) and filtered through Celite, rinsed with DCM (20 mL), dried over sodium sulfate, concentrated and purified by pre-HPLC to give the desired product (17 mg, 7%) as a white solid. NMR (300 MHz, CDC ): delta 8.41-8.40 (m, 1 H), 8.31 (d, J= 9 Hz, 1 H), 8.09-8.06 (m, 3 H), 7.82 (d, J= 11.7 Hz, 1 H), 7.38-7.34 (m, 1 H), 3.28-3.26 (m, 4 H), 3.19-3.14 (m, 2 H), 2.76-2.74 (m, 4 H), 2.63- 2.58 (m, 4 H), 1.74 (s, 6 H), 1.26-1.20 (m, 3 H). LCMS: (M+H)+ = 504.8. HPLC: 96.3%.

Molecular Weight:206.29
XLogP3:0.8
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:2
Exact Mass:206.153146591
Monoisotopic Mass:206.153146591
Topological Polar Surface Area:45.4
Heavy Atom Count:15
Complexity:189
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes